Abuse-deterrent pharmaceutical compositions of opioids and other drugs

ABSTRACT

An abuse-deterrent pharmaceutical composition has been developed to reduce the likelihood of improper administration of drugs, especially drugs such as opiods. In the preferred embodiment, a drug is modified to increase its lipophilicity. In preferred embodiments the modified drug is homogeneously dispersed within microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments the drug containing microparticles or drug particles are coated with one or more coating layers, where at least one coating is water insoluble and preferably organic solvent insoluble, but enzymatically degradable by enzymes present in the human gastrointestinal tract. The abuse-deterrent composition retards the release of drug, even if the physical integrity of the formulation is compromised (for example, by chopping with a blade or crushing) and the resulting material is placed in water, snorted, or swallowed. However, when administered as directed, the drug is slowly released from the composition as the composition is broken down or dissolved gradually within the GI tract by a combination of enzymatic degradation, surfactant action of bile acids, and mechanical erosion.

This application claims priority to U.S. Ser. No. 60/393,876 filed Jul.5, 2002 entitled “Abuse-Resistant Formulations of Oxycontin and OtherDrugs” by Alexander M. Klibanov, Stephen L. Buchwald, Timothy M. Swager,and Whe-Yong Lo; U.S. Ser. No. 60/436,523 filed Dec. 23, 2002 by AlisonB. Fleming, Roman V. Rariy, Alexander M. Klibanov, Whe-Yong Lo, and JaneHirsh; U.S. Ser. No. 60/443,226 filed Jan. 28, 2003 by Jane Hirsh,Alison B. Fleming, Alexander M. Klibanov, and Who-Yong Lo; U.S. Ser. No.60/463,514 filed Apr. 15, 2003 by Jane C. Hirsh, Alison B. Fleming,Roman V. Rariy, Stephen L. Buchwald, and Timothy M. Swager; and U.S.Ser. No. 60/463,518 filed Apr. 15, 2003 by Jane C. Hirsh, Alison B.Fleming and Roman V. Rariy.

BACKGROUND OF THE INVENTION

The present invention is generally in the field of pharmaceuticalcompositions, and specifically relates to compositions that are designedto reduce the potential for improper administration of drugs that aresubject to abuse.

Oxycodone, morphine, and other opiod analgesics are successful andtherapeutically useful medications, e.g., as pain killers, whenadministered orally. Unfortunately, they also pose a severe threat forwillful abuse due to their ability to alter mood and/or cause a sense ofeuphoria. Currently available sustained release formulations of suchdrugs, which contain a relatively large amount of drug meant to bereleased from the formulation over an extended time period, areparticularly attractive to abusers since the sustained release actioncan be destroyed by crushing or grinding the formulation. The resultingmaterial (ie, the crushed formulation) can no longer control the releaseof drug. Depending on the drug, abusers can then (1) snort the material,(2) swallow the material or (3) dissolve the material in water andsubsequently inject it intravenously. The dose of drug contained in theformulation is thus absorbed immediately through the nasal or GI mucosa(for snorting or swallowing, respectively) or is administered in a bolusto the systemic circulation (for IV injection). These abuse methodsresult in the rapid bioavailability of relatively high doses of drug,giving the abuser a “high”. Since relatively simple methods (crushing,grinding, chewing and/or dissolution in water) can be used to transformsuch formulations into an abusable form, they provide virtually nodeterrent to a potential abuser.

For example, the FDA recently strengthened the warnings and precautionssections in the labeling of OxyContin® (oxycodone HClcontrolled-release) Tablets, a narcotic drug approved for the treatmentof moderate to severe pain, because of continuing reports of abuse anddiversion. OxyContin® contains oxycodone HCl (available in 10, 20, 40and 80 mg strengths), an opioid agonist with an addiction potentialsimilar to that of morphine. Opioid agonists are substances that act byattaching to specific proteins called opioid receptors, which are foundin the brain, spinal cord, and gastrointestinal tract. When these drugsattach to certain opioid receptors in the brain and spinal cord they caneffectively block the transmission of pain messages to the brain.OxyContin® is supplied in a controlled-release dosage form and isintended to provide up to 12 hours of relief from moderate to severepain. The warning specifically states that the tablet must be takenwhole and only by mouth. When the tablet is chewed or crushed and itscontents are swallowed, snorted into the nostrils or dissolved andsubsequently injected intravenously, the controlled release mechanism isdestroyed and a potentially lethal dose of oxycodone becomesbioavailable.

In recent years, there have been numerous reports of Oxycodone diversionand abuse in several states. For example, DEA's Office of DiversionControl reported 700 OxyContin® thefts in the US between January 2000and June 2001. Some of these reported cases have been associated withserious consequences including death.

Oxycodone is a controlled substance in Schedule II of the ControlledSubstances Act (CSA), which is administered by the Drug EnforcementAdministration (DEA). Despite the fact that Schedule II provides themaximum amount of control possible under the CSA for approved drugproducts, in practice it is difficult for law enforcement agencies tocontrol the diversion or misuse of legitimate prescriptions. Althoughabuse, misuse, and diversion are potential problems for all opioids,including Oxycodone, opioids are a very important part of the medicalarmamentarium for the management of pain when used appropriately underthe careful supervision of a physician.

Currently available formulations for such drugs are designed for oraladministration but do not include mechanisms to prevent or retardimproper methods of administration such as chewing, injection andsnorting. This represents a serious problem given the large number oflegitimate prescriptions written in the US; for example, the medical useof opiods within the US increased 400% from 1996 to 2000. The problemswith abuse are significant and longstanding, and efforts to design newabuse-resistant or abuse-deterrent formulations have been largelyunsuccessful. U.S. Pat. Nos. 3,980,766, 4,070,494 and 6,309,668 describeformulations designed to prevent the injection of compositions meant fororal administration. U.S. Pat. No. 3,980,766 describes the incorporationof an ingestible solid which causes a rapid increase in viscosity uponconcentration of an aqueous solution thereof. U.S. Pat. No. 4,070,494describes the incorporation of a non-toxic, water gelable material in anamount sufficient to render the drug resistant to aqueous extraction.U.S. Pat. No. 6,309,668 describes a tablet for oral administrationcontaining two or more layers comprising one or more drugs and one ormore gelling agents within separate layers of the tablet. The resultingtablet forms a gel when combined with the volume of water necessary todissolve the drug; this formulation thus reduces the extractability ofthe drug from the tablet. It should be noted that although thesecompositions preclude abuse by injections, this approach fails toprevent abuse by crushing and swallowing or snorting the formulation,which are commonly reported methods of abuse associated with OxyContin®.

U.S. Pat. Nos. 3,773,955 and 3,966,940 describe formulations containinga combination of opiod agonists and antagonists, in which the antagonistdoes not block the therapeutic effect when the admixture is administeredorally, but which does not produce analgesia, euphoria or physicaldependence when administered parenterally by an abuser. U.S. Pat. No.4,457,933 describes a method for decreasing both the oral and parenteralabuse potential of strong analgetic agents by combining an analgesicdose of the analgetic agent with an antagonist in specific, relativelynarrow ratios. U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494describe oral dosage forms including a combination of an orally activeopiod agonist and an orally active opiod antagonist in a ratio that,when delivered orally, is analgesically effective but that is aversivein a physically dependent subject. While such a formulation may besuccessful in deterring abuse, it also has the potential to produceadverse effects in legitimate patients.

It is therefore an object of the present invention to provide apharmaceutical composition that significantly reduces the potential forimproper administration or use of drugs but which, when administered asdirected, is capable of delivering a therapeutically effective dose.

SUMMARY OF THE INVENTION

An abuse-deterrent pharmaceutical composition and the method of makingand using the composition have been developed. The composition can beused to reduce the likelihood of improper administration of drugs,especially drugs such as oxycodone. The technology is useful for anumber of other drugs where sustained release oral delivery is desired,and there is the potential for abuse if the drug dose is madeimmediately available for nasal , IV or oral administration. In thepreferred embodiment, the drug is chemically modified to increase itslipophilicity. In other embodiments, the formulation contains lipophilicor water-insoluble materials or is made using a process which increasesthe lipophilicity and/or water-insolubility of the composition.

The abuse-deterrent composition retards the release of drug, even if thephysical integrity of the dosage form is compromised (for example, bychopping with a blade or crushing) and the resulting material is placedin water, snorted, or swallowed. The composition thus provides adeterrent to common methods of improper administration including IVinjection of drug dissolved in water and nasal or oral administration ofthe crushed formulation since drug will not be immediately released fromthe formulation. However, when administered as directed, the drug isslowly released (typically over a period of 4-18 hours) from thecomposition as the composition is broken down or dissolved graduallywithin the GI tract by a combination of enzymatic degradation,surfactant action of bile acids, and mechanical erosion.

In some embodiments, the individual drug-containing microparticles ordrug particles are coated with one or more independent coating layers.At least one of the coating materials is water-insoluble and preferablyorganic solvent-insoluble, but enzymatically degradable. The componentsof the resulting coated microparticles are not mutually soluble inwater, organic solvents, or any combination thereof, so that in vitrodegradation of the formulation will require more than one step. Hencethe drug is not easily extractable from such a formulation byconventional chemical means. In contrast, when administered to thegastrointestinal tract via swallowing, the drug gradually will bereleased from the coated microparticles as a consequence of enzymaticdegradation, surfactant action of bile acids and mechanical erosionwithin the GI tract.

The pharmaceutical composition, when administered orally, results in adesired drug release profile. Such a release profile provides atherapeutic effect for an extended period of time, typically from 6 to24 hours. Additional compositions are provided which achieve a smallimmediate dose that precedes the sustained release of drug. Thecompositions disclosed herein may optionally comprise a drug having noappreciable abuse potential.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1A is a structural schematic of zinc bis-oxycodone.

FIG. 1B is a structural schematic of zinc oxycodone stearate.

FIG. 1C is a structural schematic of zinc oxycodone di-stearate.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein are an abuse-deterrent pharmaceutical composition andthe method of making and using the composition.

I. Compositions

As used herein, “composition” refers to the drug dosage unit foradministration to a patient. This may also be used in reference solelyto the active ingredient, or to the formulation containing the activeingredient.

The currently available sustained release dosage forms containingnarcotic analgesics and other drugs are subject to misuse, in part,because mechanical destruction of the dosage form exposes theencapsulated drug and allows for immediate dissolution of the drug intoaqueous media. Two properties of the dosage form that contribute to thisoutcome are (1) the ease with which drug is exposed to the extractionmedia and (2) the high water solubility of the drug salt form.

In the composition disclosed herein, one or both of these properties arealtered in order to achieve an abuse-deterrent composition.Specifically, in the preferred embodiment, the drug is modified toincrease its lipophilicity and, in additional preferred embodiments, isthen homogeneously dispersed within a material that is either slowlysoluble or not soluble in water and subsequently formulated intomicroparticles. The drug may be present in the form of discreteparticles or may be partially or fully dispersed in the carrier materialon a molecular level.

The terms “abuse-deterrent composition” or “abuse-deterrent formulation”are used interchangeably herein to refer to compositions that reduce thepotential for improper administration of drugs but that deliver atherapeutically effective dose when administered as directed. Improperadministration includes tampering with the dosage form and/oradministering the drug by any route other than instructed. For example,for a tablet or capsule, methods of tampering with the dosage :form mayinclude, but are not limited to, breaking, crushing, grinding, chewingand/or dissolving the tablet or the contents of the capsule. For oraladministration, improper administration includes administering the drugby any route other than via swallowing.

The abuse deterrent composition preferably comprises a drug modified toincrease its lipophilicity. In other preferred embodiments, the drug ishomogenously dispersed within microparticles composed of a material thatis either slowly soluble in water or water insoluble. The compositionsslow the release of drug if the dosage form is chopped or crushed andthe resulting material is placed in water, snorted, or swallowed sincemost of the drug will remain associated with or entrapped withinportions of the core material of the microparticles. In some embodimentsthe drug containing microparticles or individual drug particles arecoated with one or more coating layers, where at least one coating iswater insoluble and preferably organic solvent insoluble, butenzymatically degradable. The components of the resulting coatedmicroparticles are not mutually soluble in water, organic solvents, orany combination thereof, such that no one solvent or enzyme solution iscapable of dissolving the formulation in its entirety in vitro. Itfollows that extraction of the drug from the formulation cannot becarried out in one step. However, when administered as directed, thedrug is slowly released from the formulation since it is eroded withinthe environment of the gastrointestinal tract.

A. Drugs to be Formulated

There are many drugs that it is desirable to deliver using thecompositions described herein. The Controlled Substances Act (CSA),Title II of the Comprehensive Drug Abuse Prevention and Control Act of1970, places all substances that are regulated under existing federallaw into one of five schedules based upon the substance's medicinalvalue, harmfulness, and potential for abuse or addiction. Drugs that arepreferred include those classified as Schedule II, III, IV and V drugs.Drugs that are most preferable include those, like oxycodone, that arecurrently formulated as sustained or controlled release compositions,where drug release is intended to occur over a prolonged period of timethrough the gastrointestinal tract, and immediate or burst release, forexample, by inhalation or injection, is undesirable. As used herein,drugs prone to abuse refer to controlled substance specified as scheduleII, II, IV and V drugs.

The terms “drug”, “active agent”, and “pharmacologically active agent”are used interchangeably herein to refer to a chemical compound thatinduces a desired pharmacological, physiological effect. The terms alsoencompass pharmaceutically acceptable derivatives of those active agentsspecifically mentioned herein, including, but not limited to, salts,solvates, hydrates, complexes with one or more molecules, prodrugs,active metabolites, analogs, and the like. When the terms “activeagent”, “pharmacologically active agent” and “drug” are used, or when aparticular drug, such as oxycodone, is identified, it is to beunderstood as including the active agent per se as well aspharmaceutically acceptable salts, solvates, hydrates, complexes withone or more molecules, prodrugs, active metabolites, and analogs.

Examples of preferred drugs include,1-phenylcyclohexylamine,-piperidinocyclohexanecarbonitrile, alfentanil,alphacetylmethadol, alphaprodine, alprazolam, amobarbital, amphetamine,anileridine, apomorphine, aprobarbital, barbital, barbituric acidderivative, bemidone, benzoylecgonine, benzphetamine, betacetylmethadol,betaprodine, bezitramide, bromazepam, buprenorphine, butabarbital,butalbital, butorphanol, camazeparm, cathine, chloral, chlordiazepoxide,clobazam, clonazepam, clorazepate, clotiazepam, cloxazolam, cocaine,codeine, chlorphentermine, delorazepam, dexfenfluramine, dextromoramide,dextropropoxyphen, dezocine, diazepam, diethylpropion, difenoxin,dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, dipanone,diphenoxylate, diprenorphine, ecgonine, enadoline, eptazocine,estazolam, ethoheptazine, ethyl loflazepate, ethylmorphine, etorphine,femproponex, fencamfamin, fenfluramine, fentanyl, fludiazepam,flunitrazepam, flurazepam, glutethimide, halazepam, haloxazolam,hexalgon, hydrocodone, hydromorphone, isomethadone, hydrocodone,ketamine, ketazolam, ketobemidone, levanone, levoalphacetylmethadohl,levomethadone, levomethadyl acetate, levomethorphan, levorphanol,lofentanil, loperamide, loprazolam, lorazepam, lormetazepam, lysergicacid, lysergic acid amide, mazindol, medazepam, mefenorex, meperidine,meptazinol, metazocine, methadone, methamphetamine, methohexital,methotrimeprazine, methyldihydromorphinone, methylphenidate,methylphenobarbital, metopon, morphine, nabilone, nalbuphine, nalbupine,nalorphine, narceine, nefopam, nicomorphine, nimetazepam, nitrazepam,nordiazepam, normethadone, normorphine, oxazepam, oxazolam, oxycodone,oxymorphone, pentazocine, pentobarbital, phenadoxone, phenazocine,phencyclidine, phendimetrazine, phenmetrazine, pheneridine, piminodine,prodilidine, properidine, propoxyphene, racemethorphan, racemorphan,racemoramide, remifentanil, secobarbital, sufentanil, talbutal,thebaine, thiamylal, thiopental, tramadol, trimeperidine, andvinbarbital.

In addition to the compounds above, the following scheduled drugs may beincorporated into the composition: allobarbitone, alprazolam,amylobarbitone, aprobarbital, barbital, barbitone, benzphetamine,brallobarbital, bromazepam, brotizolam, buspirone, butalbital,butobarbitone, butorphanol, camazepam, eaptodiame, carbromal,carfentanil, carpipramine, cathine, chloral, chloral betaine, chloralhydrate, chloralose, chlordiazepoxide, chlorhexadol, chlormethiazoleedisylate, chlormezanone, cinolazepam, clobazam, potassium clorazepate,clotiazepam, cloxazolarn, cyclobarbitone, delorazepam, dexfenfluramine,diazepam, diethylpropion, difebarbarnate, difenoxin, enciprazine,estazolam, ethyl loflazepate, etizolam, febarbamate, fencamfamin,fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam,flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide,halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone, ketazolam,loprazolam mesylate, lorazepam, lormetazepam, mazindol, mebutamate,medazepam, mefenorex, mephobarbital, meprobamate, metaclazepam,methaqualone, methohexital, methylpentynol, methylphenobarbital,midazolam, milazolam, morphine, nimetazepam, nitrazepam, nordiazepam,oxazepam, oxazolam, paraldehyde, pemoline, pentabarbitone, pentazocine,pentobarbital, phencyclidine, phenobarbital, phendimetrazine,phenmetrazine, phenprobamate, phentermine, phenyacetone, pinazepam,pipradol, prazepam, proxibarbal, quazepam, quinalbaritone, secobarbital,secbutobarbitone, sibutramine, temazepam, tetrazeparn, triazolam,triclofos, zalepan, zaleplon, zolazepam, zolpidem, and zopiclone.Certain compounds described herein may exist in particular geometric orstereoisomeric forms. The composition disclosed herein contemplates allsuch compounds, including cis- and trans-isomers, R- and S-enantiomers,diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof,compounds of different spacial conformations, and other mixturesthereof, as falling within the scope of the invention. Additionalasymmetric carbon atoms may be present in a substituent such as an alkylgroup. All such isomers, as well as mixtures thereof, are intended to beincluded in this invention.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, inalic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,tolunesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000, p. 704, the disclosure of which is herebyincorporated by reference.

Optionally, the composition described herein can further include a drughaving no appreciable abuse potential.

B. Drug Solubility Modification

In preferred embodiments, the solubility characteristics of a drug arealtered prior to incorporation into the formulation. Modification of thedrug to produce a more lipophilic derivative serves to reduce the watersolubility of the drug and thus reduces the aqueous extractability.Furthermore, if the drug is made more lipophilic, it can be solubilizedin a molten fatty substance or wax like mixture, rather than physicallydispersed in a particulate form. Solubilization of drug enhances theabuse-deterrent properties of microparticles formulated from the mixtureas it is difficult to extract drug from an intimately dispersedcomposition.

The terms “lipophilic derivative” and “lipophililic drug derivative”, asused herein, refer to derivatives of the drug that are less soluble inwater than the most soluble salt of the drug. The most soluble saltbeing selected from either drug alkaline metal salts (for acidic drugs)or salts of the drug with inorganic acids (for basic drugs). Theexamples of the latter include but are not limited to hydrohalates,sulfates, and nitrates.

Some of the methods that can be used to alter the drug's lipophilicityare outlined below. It is understood that two or more approaches can becombined to achieve a desired solubility profile.

Methods for Increasing Lipophilicity

In one embodiment, drug is made more lipophilic by eliminating orreducing the overall charge of the drug molecule. For example, for abasic drug, a water soluble salt (such as hydrochloride, sulfate, ormaleate) can be converted to a free base using techniques known in theart. Correspondingly, in the case of an acidic drug, a water solublesalt (such sodium, potassium, or the like) can be converted to a freeacid.

In another embodiment, the drug's lipophilicity is increased by forminga salt between a drug molecule and a charged lipophilic compound. Inthis case the lipophilicity of the resulting salt can be manipulated byvarying the lipophilicity of the counter-ion. In general lipophilicacids or amines with chain lengths between C₅-C₃₀ are lipophiliccounter-ion candidates. Some specific examples include, but are notlimited to, linoleic acid, octanoic acid, lauric acid, stearic acid,palmitic acid, oleic acid, octyl amine, lauryl amine, stearyl amine,palmityl amine, linoleyl amine, and oleyl amine. Other salts which mayincrease lipophilicity and, hence, lipid solubility relative to theparent drug compound include, but are not limited to, pectinate,tannate, phytate, salicylate, saccharinate, acesulfamate, gallate, andterephthalate salts.

In yet another embodiment the lipophilicity of the drug is increased byforming a stable complex between a drug molecule (either charged oruncharged) and a metal cation such as zinc, magnesium, calcium, bismuthor the like. This complex may consist of one or more drug molecules, oneor more metal cations, and, optionally, one or more lipophilic chargedspecies. The aforementioned charged lipophilic species are incorporatedinto the complex if necessary to bring the charge of the final complexto zero and increase its overall lipophilicity. In general lipophilicacids or amines with chain lengths between C₅-C₃₀ are lipophiliccounter-ion candidates. Examples of such complexes for a narcotic drugoxycodone are given in FIG. 1; a lipophilic drug complex may be composedof one or two oxycodone molecules, one Zn²⁺ cation, and one or twostearate anions. It is understood by one skilled in the art that variousmetal cations as well as lipophilic counter-ions can be used to formcomplexes with an analogous structure, for example, oxymorphone.

In still a further embodiment, drug lipophilicity is increased viacomplexation with poorly water-soluble cyclodextrin. For example,ethylated beta-cyclodextrin has been shown to decrease aqueoussolubility of complexed drug molecules.

In another embodiment, a drug is covalently modified to increase itslipophilicity. For example, a lipophilic compound can be covalentlyattached to a drug molecule via an ester or amide linkage. Such drugderivatives are cleaved in vivo, thus releasing the parent compound.

C. Drug Containing Microparticles

In preferred embodiments, drugs are formulated with a carrier materialto form microparticles. As used herein, the term “microparticle” refersto a composition comprising a drug dispersed within a carrier materialand “coated microparticle” refers to a composition comprising a drugcontaining microparticle or a drug particle coated with one or morecoating layers of material. Microparticles and coated microparticleshave a size range of 10 to 3000 microns in diameter.

Within microparticles, drug is preferably homogeneously dispersed in theform of fine particles within the carrier material. More preferably,drug is partially solubilized in molten carrier material or partiallydissolved with the carrier material in a mutual solvent during theformulation of the microparticles. Most preferably, drug is completelysolubilized in the molten carrier material or completely dissolved withthe carrier material in a co-solvent during the formulation of themicroparticles. This is accomplished through the selection of materialsand the manner in which they are processed.

Carrier materials appropriate for the fabrication of drug containingmicroparticles are either slowly soluble in water or insoluble in water,but capable of degrading within the GI tract by means includingenzymatic degradation, surfactant action of bile acids and mechanicalerosion. As used herein, the term “slowly soluble in water” refers tomaterials that are not dissolved in water within a period of 30 minutes.Preferred examples include fats, fatty substances, waxes, wax-likesubstances and mixtures thereof. Suitable fats and fatty substancesinclude fatty alcohols (such as lauryl, myristyl stearyl, cetyl orcetostearyl alcohol), fatty acids and derivatives, including but notlimited to fatty acid esters, fatty acid glycerides (mono-, di- andtri-glycerides), and hydrogenated fats. Specific examples include, butare not limited to hydrogenated vegetable oil, hydrogenated cottonseedoil, hydrogenated castor oil, hydrogenated oils available under thetrade name Sterotex®, stearic acid, cocoa butter, and stearyl alcohol.Suitable waxes and wax-like materials include natural or syntheticwaxes, hydrocarbons, and normal waxes. Specific examples of waxesinclude beeswax, glycowax, castor wax, carnauba wax, paraffins andcandelilla wax. As used herein, a wax-like material is defined as anymaterial which is normally solid at room temperature and has a meltingpoint of from about 30 to 300° C.

In some cases, it may be desirable to alter the rate of waterpenetration into the hydrophobic drug containing microparticles. To thisend, rate-controlling (wicking) agents may be formulated along with thefats or waxes listed above. Examples of rate-controlling materialsinclude certain starch derivatives (eg, waxy maltodextrin and drum driedcorn starch), cellulose derivatives (eg, hydroxypropylmethylcellulose,hydroxypropylcellulose, methylcellulose, and carboxymethylcellulose),alginic acid, lactose and talc. Additionally, a pharmaceuticallyacceptable surfactant (for example, lecithin) may be added to facilitatethe degradation of such microparticles.

Proteins which are water insoluble, such as zein, are preferred carriermaterials for the formation of drug containing microparticles.Additionally, proteins, polysaccharides and combinations thereof whichare water soluble can be formulated with drug into microparticles andsubsequently cross-linked to form an insoluble network. For example,cyclodextrins can be complexed with individual drug molecules andsubsequently cross-linked.

Certain polymers may also be used as carrier materials in theformulation of drug containing microparticles. Suitable polymers includeethylcellulose and other natural or synthetic cellulose derivatives.Polymers which are slowly soluble and form a gel in an aqueousenvironment, such as hydroxypropyl methylcellulose or polyethylene oxidemay also be suitable as carrier materials for drug containingmicroparticles.

Encapsulation or incorporation of drug into carrier materials to producedrug containing microparticles can be achieved through knownpharmaceutical formulation techniques. To create a composition thatprotects drug from exposure upon mechanical disruption (eg, grinding,chewing, or chopping), the drug is intimately dispersed within thecarrier material. In the case of formulation in fats, waxes or wax-likematerials, the carrier material is heated above its melting temperatureand the drug is added to form a mixture comprising drug particlessuspended in the carrier material, drug dissolved in the carriermaterial, or a mixture thereof. Microparticles can be subsequentlyformulated through several methods including, but not limited to, theprocesses of congealing, extrusion, spray chilling or aqueousdispersion. In a preferred process, wax is heated above its meltingtemperature, drug is added, and the molten wax-drug mixture is congealedunder constant stirring as the mixture cools. Alternatively, the moltenwax-drug mixture can be extruded and spheronized to form pellets orbeads. Detailed descriptions of these processes can be found in“Remington—The science and practice of pharmacy”, 20th Edition, Jennaroet. Al., (Phila, Lippencott, Williams, and Wilkens, 2000).

For some carrier materials it may be desirable to use a solventevaporation technique to produce drug containing microparticles. In thiscase drug and carrier material are co-dissolved in a mutual solvent andmicroparticles can subsequently be produced by several techniquesincluding, but not limited to, forming an emulsion in water or otherappropriate media, spray drying or by evaporating off the solvent fromthe bulk solution and milling the resulting material.

In addition to modification of the drug itself, processing conditionscan be used to influence the dispersion of the drug withinwater-insoluble or slowly water soluble material. For example, in thecase where the water in-soluble or slowly soluble material is melted anddrug is fully or partially dissolved under stirring conditions, thetemperature, agitation rate and time of processing will influence thedegree of dissolution achieved. More specifically, a more homogenousdispersion may be achieved with a higher temperature, faster stirringrate and longer processing time. Ultrasound can also be applied to themolten mixture to increase the degree of dispersion and/or the rate ofdissolution of the drug.

In some embodiments, drug in a particulate form is homogeneouslydispersed in a water-insoluble or slowly water soluble material. Tominimize the size of the drug particles within the composition, the drugpowder itself may be milled to generate fine particles prior toformulation. The process of jet milling, known in the pharmaceuticalart, can be used for this purpose. In some embodiments drug in aparticulate form is homogeneously dispersed in a wax or wax likesubstance by heating the wax or wax like substance above its meltingpoint and adding the drug particles while stirring the mixture. In thiscase a pharmaceutically acceptable surfactant may be added to themixture to facilitate the dispersion of the drug particles.

D. Coated Drug Containing Microparticles

In some embodiments, drug containing microparticles or drug particlesare encapsulated within at least one water-insoluble enzymaticallydegradable material. In some instances the substrates of digestiveenzymes are naturally water-insoluble and can be utilized in theformulation without further processing. Solid esters of fatty acids,which are hydrolyzed by lipases, can be spray coated onto microparticlesor drug particles. Zein is an example of a naturally water-insolubleprotein. It can be coated onto drug containing microparticles or drugparticles by spray coating or by wet granulation techniques. In additionto naturally water-insoluble materials, some substrates of digestiveenzymes can be treated with cross-linking procedures, resulting in theformation of non-soluble networks. Many methods of cross-linkingproteins, initiated by both chemical and physical means, have beenreported. One of the most common methods to obtain cross-linking is theuse of chemical cross-linking agents. Examples of chemical cross-linkingagents include aldehydes (gluteraldehyde and formaldehyde), epoxycompounds, carbodiimides, and genipin. In addition to thesecross-linking agents, oxidized and native sugars have been used tocross-link gelatin (Cortesi, R., et al., Biomaterials 19 (1998)1641-1649). Cross-linking can also be accomplished using enzymaticmeans; for example, transglutaminase has been approved as a GRASsubstance for cross-linking seafood products. Finally, cross-linking canbe initiated by physical means such as thermal treatment, UV irradiationand gamma irradiation.

To produce a coating layer of cross-linked protein surrounding drugcontaining microparticles or drug particles, a water soluble protein canbe spray coated onto the microparticles and subsequently cross-linked bythe one of the methods described above. Alternatively, drug containingmicroparticles can be microencapsulated within protein bycoacervation-phase separation (for example, by the addition of salts)and subsequently cross-linked. Some suitable proteins for this purposeinclude gelatin, albumin, casein, and gluten.

Polysaccharides can also be cross-linked to form a water-insolublenetwork. For many polysaccharides, this can be accomplished by reactionwith calcium salts or multivalent cations which cross-link the mainpolymer chains. Pectin, alginate, dextran, amylose and guar gum aresubject to cross-linking in the presence of multivalent cations.Complexes between oppositely charged polysaccharides can also be formed;pectin and chitosan, for example, can be complexed via electrostaticinteractions. Insoluble coatings can be formed on particles in thisfashion. It should be noted that in many cases polysaccharides arebroken down specifically by enzymes produced by bacteria within thecolon.

In some cases a water-insoluble but enzymatically degradable coatingcomprising both a protein and a polysaccharide can be produced if thecomponents are oppositely charged polyelectrolytes. Under the propertemperature, pH, and concentrations, the two polymers can interactthrough their opposite electrical charges and form a water-insolublecomplex. If a core particle is present at the time the complex phaseseparates, it will be coated. For example, gelatin and gum arabic can becoated onto a core particle utilizing this process. Optionally, thecomplex can be made irreversibly insoluble by subsequent cross-linkinginduced by chemical or physical means.

E. Dosage Forms

There are a number of drug compositions that meet the abuse deterrentcriteria outlined above. In one embodiment a drug is homogeneouslydispersed, in a fine particulate form, within a water-insoluble orslowly water soluble material and the mixture is formulated intomicroparticles. In another embodiment a drug is partially dissolvedwithin a water-insoluble or slowly water soluble material during themanufacturing process, for example, by mixing at a temperature above themelting point of the carrier material, and the mixture is formulatedinto microparticles. In yet another embodiment a drug is fully dissolvedwithin a water-insoluble or slowly water soluble material during themanufacturing process, for example, by mixing at a temperature above themelting point of the carrier material, and the mixture is formulatedinto microparticles. In still a further embodiment, the drug containingmicroparticles, where the drug is homogeneously dispersed in aparticulate form, or has been partially or fully dissolved within thecarrier material during the manufacturing process, are coated with oneor more coatings to form coated microparticles. In a further embodiment,drug particles are coated directly with one or more coatings to formcoated microparticles.

The microparticles, coated microparticles, or a mixture thereof areformed into a solid dosage form suitable for oral administration. Forexample, microparticles or coated microparticles can be incorporatedinto hard capsules, dispersed within a soft gelatin capsule, or combinedwith appropriate excipients and tableted by compression.

In some embodiments, the compositions are coated with an entericcoating. Enteric coatings known in the art are applied directly to theabuse-deterrent microparticle or coated microparticle compositions orare applied to the surface of a capsule or tablet comprising the abusedeterrent microparticle and/or coated microparticle compositions.Enteric coatings known in the art include, for example, acrylic polymersthat are commercially available under the trade name EUDRAG1T®,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,polyvinyl acetate phthalate, shellac, hydroxypropylmethylcellulosesuccinate, cellulose acetate trimelliate or mixtures thereof.

Dosage forms can include one or more drugs. When the dosage formincludes two or more drugs they can be Scheduled drugs or can be acombination of Scheduled and non-Scheduled drugs. The drugs can beincorporated into separate microparticle compositions where theScheduled drugs are incorporated into abuse deterrent microparticlecompositions and the non-Scheduled drugs are incorporated into abusedeterrent microparticle compositions, sustained release compositionsknown in the art or immediate release compositions known in the art. Thecompositions comprising the different drugs are formulated into a singlesolid dosage form suitable for oral administration, for example, theycan be incorporated into a gelatin capsule, or combined with appropriateexcipients and compressed into a tablet form. Examples of non-scheduleddrugs that may be included in dosage forms described herein include, butare not limited to, aspirin, acetaminophen, non-steroidalanti-inflammatory drugs, cyclooxygenase II inhibitors,N-methyl-D-aspartate receptor antagonists, glycine receptor antagonists,triptans, dextromethorphan, promethazine, fiorinal, guaifenesin,butalbital, and caffeine.

An immediate release dose can be incorporated into the formulation inseveral ways. Immediate release microparticles can be made utilizingstandard methodologies and formulated along with abuse-deterrentmicroparticle and/or coated microparticle compositions in a suitableoral dosage form. Alternatively, a coating containing drug which isavailable for immediate release can be placed on a tablet comprisingabuse-deterrent microparticle and/or coated microparticle compositionsplus appropriate excipients. Additionally, an immediate dose of drug canbe granulated or blended with rapidly dissolving excipients andsubsequently compressed (1) as one layer of bi-layer tablets in whichthe abuse-deterrent microparticle and/or coated microparticlecompositions are compressed as the other layer, or (2) as the outerlayer of compression-coated tablets in which the abuse-deterrentmicroparticle and/or coated microparticle compositions are compressed asthe inner core, or (3) into tablets in which abuse-deterrentmicroparticle and/or coated microparticle compositions are embedded.

In some embodiments, the immediate release portion of the dosage formcomprises a lipophilic drug derivative. For example, salt derivatives orcomplexes that are insoluble at a neutral pH but dissociate, therebyreleasing the parent compound, at an acidic pH are ideal for immediaterelease within the stomach. In the case of oxycodone some salts that mayexhibit this property include, but are not limited to, the tannate,phthalate, salicylate, gallate, pectinate, phytate, saccharinate,asesulfamate and terephthalate salts. Complexes of drug with one or moremetal ions and, optionally, one or more lipophilic counter-ions (see,for example, FIG. 1) may also be used for immediate drug release. Use ofsalts or complexes in the immediate release portion of the dosage formreduces the abuse potential of the immediate release dose if theformulation is crushed and (1) snorted or (2) dissolved in water sincethese salts will be poorly soluble under these conditions. It isunderstood by the one of ordinary skill in the art that such salts orcomplexes may also be used to formulate an immediate release dosage formwithout a sustained release portion.

Additional mechanisms to reduce the potential for abuse can also beincorporated during the process of formulating tablets. For example,ingredients can be added to deter chewing or snorting of the finalformulation. For example, an intensely bitter substance may deterchewing, while an intensely spicy ingredient, such as capsaicin, maydeter snorting. The addition of a colored dye, which would stain theskin and mucosal surface of the nose following snorting may also serveto reduce this practice.

Optional excipients present in the oral dosage form comprising abusedeterrent microparticles or coated microparticles include, but are notlimited to diluents, binders, lubricants, disintigrants, colorants,plasticizers and the like. Diluents, also termed “fillers,” aretypically necessary to increase the bulk of a solid dosage form so thata practical size is provided for compression of tablets. Examples ofdiluents include cellulose, dry starch, microcrystalline cellulose,dicalcium phosphate, calcium sulfate, sodium chloride confectioner'ssugar, compressible sugar, dextrates, dextrin, dextrose, sucrose,mannitol, powdered cellulose, sorbitol, and lactose. Binders are used toimpart cohesive qualities powdered materials and can include materialssuch as starch, gelatin, sugars, natural and synthetic gums,polyethylene glycol, ethylcellulose, methylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, waxes andpolyvinyl pyrrolidone. Lubricants are used to facilitate tabletmanufacture; examples of lubricants include talc, magnesium stearate,calcium stearate, hydrogenated vegetable oils stearic acid, sodiumstearyl fumarate, sodium benzoate, sodium acetate, leucine, sodiumoleate, sodium lauryl sulfate, magnesium lauryl sulfate and polyethyleneglycol. Disintegrants can be added to pharmaceutical formulations inorder to facilitate “breakup” or disintegration after administration.Materials used for this purpose include starches, clays, celluloses,aligns, gums, and cross-linked polymers. A plasticizer may be includedin coating materials to alter their mechanical properties. Examples ofplasticizers include benzyl benzoate, chlorobutanol, dibutyl sebacate,diethyl phthalate, glycerin, mineral oil, polyethylene glycol, sorbitol,triacetin, triethyl citrate, glycerol, etc. In addition to the additivesabove, coloring and flavoring agents may also be incorporated into thecomposition.

Optionally, the composition disclosed herein comprises materials whereina combination of the materials is not soluble in water, organic solvent,or any combination thereof.

II. Methods of Administration

It is assumed that upon oral ingestion of the intact composition, drugis released as the formulation is gradually broken down or dissolvedwithin the GI tract by a combination of enzymatic degradation,surfactant action of bile acids, and mechanical erosion. This is aresult of the unique ability of the human digestive system toefficiently break down or solubilize a variety of materials. The processwithin the GI tract that results in the digestion of food and theabsorption of nutrients is well known. Following mastication within themouth, food passes into the stomach where it is mixed with digestivejuices. This fluid contains the proteolytic enzyme pepsin which,following activation by the low pH within the stomach, begins theprocess of cleaving ingested proteins into smaller peptide fragments.Food then enters the small intestine in the form of macromolecularaggregates, where it is digested into molecules near or in a formcapable of being absorbed. This digestion is accomplished through theaction of various enzymes which are produced in the pancreas and flowinto the upper portion of the large intestine, the duodenum. The enzymessynthesized in the pancreas include proteases, amylases and lipases;these enzymes are capable of breaking down proteins, starches and fats,respectively. The digestion of fats is further facilitated by thesecretion of bile into the duodenum since bile salts, which contain bothhydrophobic and hydrophilic portions, are capable of emulsifying lipidsinto minute droplets in order to increase the surface area available fordigestion by lipases. The material which remains following passagethrough the small intestine enters the large intestine. Bacteria capableof breaking down carbohydrates not digested in the small intestine (suchas cellulose) are present in large numbers this region of the digestivetract. Finally, in addition to microbial fermentation, the largeintestine functions to absorb water and electrolytes and to form andstore feces until they are excreted.

In addition to providing a deterrent to common methods ofabuse/diversion, the formulation can provide a sustained release of drugover an extended time period. This is a natural consequence of the factthat, in the present formulation, drug is slowly released from apredominantly water-insoluble, hydrophobic matrix following thedegradation of the matrix. The barrier components are degraded, forexample, by enzymes, the surfactant action of bile acids and mechanicalerosion.

In some embodiments, an immediate release of drug is achieved within thestomach in order to provide rapid therapeutic onset.

The pharmaceutical drug composition is administered orally. Theappropriate dosage formulations can be obtained by calculation of thepharmacokinetics of the formulation, then adjusting using routinetechniques to yield the appropriate drug levels based on the approveddosage focus. Any suitable amount of drug containing microparticles orcoated microparticles can be included in the final formulation. Theselection of a suitable amount of drug containing microparticles dependson the dosage desired and is readily determined by those skilled in theart.

In addition to oral administration, some embodiments may also beadministered by other routes, including, but not limited to, rectal andnasal administration. Some embodiments may also be suitable forformulation as oral liquids.

The present composition and method of making and using the compositionwill be further understood by reference to the following non-limitingexamples.

EXAMPLE 1 Preparation of Lipophilic Oxycodone Derivatives

A. Oxycodone Free Base

The free base of oxycodone was prepared from its hydrochloride salt bythe following method: Oxycodone hydrochloride was dissolved in water andsodium carbonate was added in the amount required to neutralizehydrochloric acid. Methylene chloride was added in order to extract theformed oxycodone free base. The obtained organic layer was dried oversodium sulfate and methylene chloride was evaporated using rotaryevaporator. The obtained oxycodone free base was purified bycrystallization.

B. Zinc-bis-oxycodone

Zinc bis-oxycodone can be obtained in anhydrous media by reactingoxycodone free base with Zn(Et)₂

C. Zinc oxycodone stearate

Zinc oxycodone stearate can be obtained in anhydrous media by reactingoxycodone free base with Zn(Et)(C₁₈H₃₅O₂)

D. Zinc oxycodone di-stearate

Zinc-oxycodone di-stearate can be obtained by co-melting Zn(C₁₈H₃₅O₂)₂and oxycodone free base.

E. Oxycodone terephthalate

Oxycodone terephthalate is commercially available and can be usedwithout further processing

The structures of some representative oxycodone zinc complexes are shownin FIGS. 1A, 1B and 1C.

EXAMPLE 2 Preparation of Drug Containing Microparticles

The free base, salts or complexes from Example 1 are added to moltenhydrogenated vegetable oil, mixed, extruded and spheronized to form drugcontaining microparticles.

EXAMPLE 3 Preparation of Coated Drug Containing Microparticles

The drug-containing particles from Example 2 are spray coated with zeinin a fluidized bed apparatus.

EXAMPLE 4 Preparation of Capsules for Oral Administration

The drug containing microparticles from Example 2 and/or the coatedmicroparticles from Example 3 are incorporated into standard gelatincapsules.

EXAMPLE 5 Preparation of Capsules for Oral Administration Containing aDose of Drug for Immediate Release

The drug containing microparticles from Example 2 and/or the coatedmicroparticles from Example 3 are combined with immediate release drugparticles, and incorporated into standard gelatin capsules.

We claim:
 1. An orally administerable abuse-deterrent pharmaceuticalcomposition comprising a therapeutically effective amount of a drugprone to abuse selected from the group of compositions consisting of (a)a composition comprising a therapeutically effective amount of alipophilic derivative of a drug prone to abuse, and (b) awater-insoluble, preferably lipophilic, formulation comprising atherapeutically effective amount of a drug prone to abuse.
 2. Thecomposition of claim 1 comprising a therapeutically effective amount ofa lipophilic derivative of a drug prone to abuse in one or morepharmaceutically acceptable excipients.
 3. The composition of claim 1,wherein the composition is a controlled-release pharmaceuticalcomposition.
 4. The composition of claim 1, wherein the compositionprevents the immediate release of a substantial portion of incorporateddrug when the physical integrity of the composition is compromised andthe resulting material is exposed to an aqueous medium.
 5. Thecomposition of claim 4, wherein the portion of the drug releasedimmediately is less than 80% of the total amount of drug incorporatedinto formulation.
 6. The composition of claim 1, wherein the compositionprevents the immediate release of a substantial portion of incorporateddrug when the physical integrity of the composition is compromised andthe resulting material is exposed to a non-aqueous medium.
 7. Thecomposition of claim 6, wherein the portion of the drug releasedimmediately is less than 80% of the total amount of the drugincorporated into the composition.
 8. The composition of claim 1 whereinthe drug prone to abuse is selected from the group consisting of1-phenylcyclohexylamine, 1-piperidinocyclohexanecarbonitrile,alfentanil, alphacetylmethadol, alphaprodine, alprazolam, amobarbital,amphetamine, anileridine, apomorphine, aprobarbital, barbital,barbituric acid derivative, bemidone, benzoylecgonine, benzphetamine,betacetylmethadol, betaprodine, bezitramide, bromazepam, buprenorphine,butabarbital, butalbital, butorphanol, carnazepam, cathine, chloral,chlordiazepoxide, clobazam, clonazepam, clorazepate, clotiazepam,cloxazolam, cocaine, codeine, chlorphentermine, delorazepam,dexfenfluramine, dextromoramide, dextropropoxyphen, dezocine, diazepam,diethylpropion, difenoxin, dihydrocodeine, dihydromorphine, dioxaphentylbutyrate, dipanone, diphenoxylate, diprenorphine, ecgonine, enadoline,eptazocine, estazolam, ethoheptazine, ethyl loflazepate, ethylmorphine,etorphine, femproponex, fencamfamin, fenfluramine, fentanyl,fludiazepam, flunitrazepam, flurazeparn, glutethimide, halazepam,haloxazolam, hexalgon, hydrocodone, hydromorphone, isomethadone,hydrocodone, ketamine, ketazolam, ketobemidone, levanone,levoalphacetylmethadol, levomethadone, levomethadyl acetate,levomethorphan, levorphanol, lofentanil, loperamide, loprazolam,lorazepam, lormetazepam, lysergic acid, lysergic acid amide, mazindol,medazepam, mefenorex, meperidine, meptazinol, metazocine, methadone,methamphetamine, methohexital, methotrimeprazine,methyldihydromorphinone, methylphenidate, methylphenobarbital, metopon,morphine, nabilone, nalbuphine, nalbupine, nalorphine, narceine,nefopam, nicomorphine, nimetazeparm, nitrazepam, nordiazepam,normethadone, normorphine, oxazepam, oxazolam, oxycodone, oxymoiphone,pentazocine, pentobarbital, phenadoxone, phenazocine, phencyclidine,phendimetrazine, phenmetrazine, pheneridine, pirninodine, prodilidine,properidine, propoxyphene, racemethorphan, racemorphan, racemoramide,remifentanil, secobarbital, sufentanil, talbutal, thebaine, thiamylal,thiopental, tramadol, trimeperidine, vinbarbital, allobarbitone,alprazolam, amylobarbitone, aprobarbital, barbital, barbitone,benzphetamine, brallobarbital, bromazepam, brotizolam, buspirone,butalbital, butobarbitone, butorphanol, camazepam, captodiame,carbromal, carfentanil, carpipramine, cathine, chloral, chloral betaine,chloral hydrate, chloralose, chlordiazepoxide, chlorhexadol,chlormethiazole edisylate, chlormezanone, cinolazepam, clobazam,potassium clorazepate, clotiazepam, cloxazolam, cyclobarbitone,delorazepam, dexfenfluramine, diazepam, diethylpropion, difebarbamate,difenoxin, enciprazine, estazolam, ethyl lotlazepate, etizolam,febarbamate, fencamfamin, fenfluramine, fenproporex, fluanisone,fludiazepam, flunitraam, flunitrazepam, flurazepam, flutoprazepam,gepirone, glutethimide, halazepam, haloxazolam, hexobarbitone, ibomal,ipsapirone, ketazolam, loprazolam mesylate, lorazepam, lormetazepam,mazindol, mebutamate, medazepain, mefenorex, mephobarbital, meprobamate,metaclazepam, methaqualone, methohexital, methylpentynol,methylphenobarbital, midazolam, milazolam, morphine, nimetazeparn,nitrazepam, nordiazepam, oxazepam, oxazolam, paraldehyde, pemoline,pentabarbitone, pentazocine, pentobarbital, phencyclidine,phenobarbital, phendimetrazine, phenmetrazine, phenprobamate,phentermine, phenyacetone, pinazepam, pipradol, prazepam, proxibarbal,quazepam, quinalbaritone, secobarbital, secbutobarbitone, sibutramine,temazepam, tetrazepam, triazolam, triclofos, zalepan, zaleplon,zolazepam, zolpidem, and zopiclone.
 9. The composition of claim 2,wherein the lipophilic derivative of a drug is a free base or a freeacid of the drug.
 10. The composition of claim 2, wherein the lipophilicderivative of a drug is a salt comprising the ionized drug and alipophilic counter-ion.
 11. The composition of claim 2, wherein thelipophilic derivative of a drug is a complex comprising one or morecomponents selected from the group consisting of drug molecules, metalcations, and lipophilic counter-ions.
 12. The composition of claim 2,wherein the lipophilic derivative of a drug is a complex comprising oneor more components selected from the group consisting of drug molecules,metal cations, and cyclodextrin molecules.
 13. The composition of claim2 wherein the drug is complexed with a metal cation selected from thegroup consisting of zinc, calcium, magnesium, bismuth and combinationsthereof.
 14. The composition of claim 11 wherein the drug is oxycodone,and wherein the metal cation is selected from the group consisting ofzinc, calcium, magnesium, and bismuth and the lipophilic counter-ion isselected from the group consisting of stearate, oleate, palmitate,laurate and linoleate.
 15. The composition of claim 2, wherein thelipophilic derivative of a drug is a complex comprising the drug and acyclodextrin.
 16. The composition of claim 2, wherein the lipophilicderivative of a drug is an ester or amide formed between the drug and afatty acid.
 17. The composition of claim 1, wherein the drug isincorporated into a plurality of individual microparticles comprising amaterial that is either slowly soluble in water or water insoluble. 18.The composition of claim 17 wherein the microparticles comprise a wax orwax-like material.
 19. The composition of claim 17 wherein themicroparticles comprise a fat or a fatty substance.
 20. The compositionof claim 17 wherein the microparticles comprise a material selected fromthe group consisting of naturally water insoluble proteins, naturallywater insoluble polysaccharides, naturally water insoluble lipids andphospholipids, cross-linked water soluble proteins, cross-linked watersoluble polysaccharides, cross-linked water soluble cyclodextrins andcombinations thereof.
 21. The composition of claim 17 wherein theindividual microparticles are coated with one or more independentlayers, where at least one of the layers is water insoluble and isdegraded by enzymes of the human gastrointestinal tract.
 22. Thecomposition of claim 1 wherein the drug is in the form of individualdrug particles coated with one or more independent layers where at leastone of the layers is water insoluble and is degraded by enzymes of thehuman gastrointestinal tract.
 23. The composition of claim 21 wherein atleast one of the layers is water-insoluble, organic solvent-insoluble,and degradable by enzymes present in the human gastrointestinal tract.24. The composition of claim 21 comprising materials wherein acombination of these materials is not soluble in water, organic solvent,or any combination thereof.
 25. The composition of claim 21 wherein thecomposition is not completely soluble, and wherein the drug is not fullyreleased in a single solvent or enzyme solution.
 26. The composition ofclaim 21 wherein the enzymatically degradable layer(s) comprise amaterial selected from the group consisting of naturally water insolubleproteins, naturally water insoluble polysaccharides, naturally waterinsoluble lipids and phospholipids, cross-linked proteins, cross-linkedpolysaccharides, and combinations thereof.
 27. The composition of claim1 wherein the drug prone to abuse is co-administered with a drug thathas no appreciable abuse potential.
 28. The composition of claim 1formulated for the drug to be immediately released upon oraladministration.
 29. The composition of claim 1 wherein the drug prone toabuse is oxycodone.
 30. A method of manufacturing an abuse-resistantpharmaceutical composition comprising homogeneously dispersing atherapeutically effective amount of a drug prone to abuse, in one ormore pharmaceutically acceptable carrier(s), diluent(s), and/oradditives, to form an orally administerable abuse-deterrentpharmaceutical composition comprising a therapeutically effective amountof a drug prone to abuse selected from the group of compositionsconsisting of (a) a composition comprising a therapeutically effectiveamount of a lipophilic derivative of a drug prone to abuse, and (b) awater-insoluble, preferably lipophilic, formulation comprising atherapeutically effective amount of a drug prone to abuse, as defined byany of claim
 1. 31. The method of claim 30 further comprisingformulating the composition into a capsule or tablet.
 32. A method ofadministering an abuse-resistant pharmaceutical composition comprisingorally administering to a patient in need thereof an abuse-deterrentpharmaceutical composition comprising a therapeutically effective amountof a drug prone to abuse selected from the group of compositionsconsisting of (a) a composition comprising a therapeutically effectiveamount of a lipophilic derivative of a drug prone to abuse, and (b) awater-insoluble, preferably lipophilic, formulation comprising atherapeutically effective amount of a drug prone to abuse, as defined byany of claim 1.